implantation-an-isoproterenol-mini-pump-to-induce-heart-failure

Implantation of an Isoproterenol Mini-Pump to Induce Heart Failure in Mice

Isoproterenol (ISO), is a non-selective beta-adrenergic agonist, that is used widely to induce cardiac injury in mice. While the acute model mimics ...

University of California

Operationalizing Precision Cardiovascular Medicine: Three Innovations.

We previously reported a genetic analysis of heart failure traits in a population of inbred mouse strains treated with isoproterenol to mimic catecholamine-driven cardiac hypertrophy. Here, we apply a co-expression network algorithm, wMICA, to perform a systems-level analysis of left ventricular transcriptomes from these mice. We describe the features of the overall network but focus on a module identified in treated hearts that is strongly related to cardiac hypertrophy and pathological remodeling. Using the causal modeling algorithm NEO, we identified the gene Adamts2 as a putative regulator of this module and validated the predictive value of NEO using small interfering RNA-mediated knockdown in neonatal rat ventricular myocytes. Adamts2 silencing regulated the expression of the genes residing within the module and impaired isoproterenol-induced cellular hypertrophy. Our results provide a view of higher order interactions in heart failure with potential for diagnostic and therapeutic insights.

Systems Genetics Approach Identifies Gene Pathways and Adamts2 as Drivers of Isoproterenol-Induced Cardiac Hypertrophy and Cardiomyopathy in Mice.

Cardiac failure has been widely associated with an increase in glucose utilization. The aim of our study was to identify factors that mechanistically bridge this link between hyperglycemia and heart failure. Here, we screened the Hybrid Mouse Diversity Panel (HMDP) for substrate-specific cardiomyocyte candidates based on heart transcriptional profile and circulating nutrients. Next, we utilized an in vitro model of rat cardiomyocytes to demonstrate that the gene expression changes were in direct response to substrate abundance. After overlaying candidates of interest with a separate HMDP study evaluating isoproterenol-induced heart failure, we chose to focus on the gene  as a cardiomyocyte glucose utilization-specific factor.  gene knockdown in rat cardiomyocytes reduced expression and protein abundance of key glycolytic enzymes. This resulted in reduction of both glucose uptake and glycogen content in cardiomyocytes stimulated with isoproterenol. Furthermore, this reduction effectively blunted the capacity of glucose and isoprotereonol to synergistically induce hypertrophic gene expression and cell size expansion. We conclude that  serves as regulator of cardiomyocyte glycolytic activity and can consequently regulate hypertrophic response in the context of elevated glucose content. Here, we apply a novel method for screening transcripts based on a substrate-specific expression pattern to identify  as an induced cardiomyocyte glucose utilization factor. We further show that reducing expression of the gene could effectively blunt hypertrophic response in the context of elevated glucose content.

A systems genetics approach identifies  as a link between cardiomyocyte glucose utilization and hypertrophic response.

A traditional approach to investigate the genetic basis of complex diseases is to identify genes with a global change in expression between diseased and healthy individuals. However, population heterogeneity may undermine the effort to uncover genes with significant but individual contribution to the spectrum of disease phenotypes within a population. Here we investigate individual changes of gene expression when inducing hypertrophy and heart failure in 100 + strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). We find that genes whose expression fold-change correlates in a statistically significant way with the severity of the disease are either up or down-regulated across strains, and therefore missed by a traditional population-wide analysis of differential gene expression. Furthermore, those "fold-change" genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome. We validate our approach by showing that the knockdown of , predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80-90% in neonatal rat ventricular myocytes. Our results demonstrate that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies.

A personalized, multiomics approach identifies genes involved in cardiac hypertrophy and heart failure.

The goal of this review is to summarize current understanding of pharmacogenetics and pharmacogenomics in chemotherapy-induced cardiotoxicity.

Pharmacogenetics of Chemotherapy-Induced Cardiotoxicity.

Isoproterenol is used widely for inducing heart failure in mice. Isoproterenol is a nonselective beta-adrenergic agonist. The acute model mimics stress-induced cardiomyopathy. The chronic model mimics advanced heart failure in humans. In this chapter, we describe a protocol that we used to induce heart failure in 100+ strains of inbred mice. Techniques on surgical pump implantation and echocardiography are described in detail. We also discuss the impact of drug dosage, duration, mortality, age, gender, and strain on cardiac remodeling responses. The success of model creation may be assessed by echocardiogram or molecular markers. This chapter may be relevant to those who are interested in using this heart failure model.

Isoproterenol-Induced Heart Failure Mouse Model Using Osmotic Pump Implantation.

We describe a simple bioinformatics method for biomarker discovery that is based on the analysis of global transcript levels in a population of inbred mouse strains showing variation for disease-related traits. This method has advantages such as controlled environment and accessibility to heart and plasma tissue in the preclinical selection stage. We illustrate the approach by identifying candidate heart failure (HF) biomarkers by overlaying mouse transcriptome and clinical traits from 91 Hybrid Mouse Diversity Panel (HMDP) inbred strains and human HF transcriptome from the Myocardial Applied Genomics Network (MAGNet) consortium. We found that some of the top differentially expressed genes correlated with known human HF biomarkers, such as galectin-3 and tissue inhibitor of metalloproteinase 1. Using ELISA assays, we investigated one novel candidate, Glycoprotein NMB, in a mouse model of chronic β-adrenergic stimulation by isoproterenol (ISO) induced HF. We observed significantly lower GPNMB plasma levels in the ISO model compared to the control group (p-value = 0.007). In addition, we assessed GPNMB plasma levels among 389 HF cases and controls from the METabolic Syndrome In Men (METSIM) study. Lower levels of GPNMB were also observed in patients with HF from the METSIM study compared to non-HF controls (p-value < 0.0001). In summary, we have identified several candidate biomarkers for HF using the cardiac transcriptome data in a population of mice that may be directly relevant and applicable to human populations.

Jessica J. Wang

Department of Medicine

University of California

Implantation of an Isoproterenol Mini-Pump to Induce Heart Failure in Mice